TY - JOUR
T1 - Population-level variation in enhancer expression identifies disease mechanisms in the human brain
AU - the CommonMind Consortium
AU - Dong, Pengfei
AU - Hoffman, Gabriel E.
AU - Apontes, Pasha
AU - Bendl, Jaroslav
AU - Rahman, Samir
AU - Fernando, Michael B.
AU - Zeng, Biao
AU - Vicari, James M.
AU - Zhang, Wen
AU - Girdhar, Kiran
AU - Townsley, Kayla G.
AU - Misir, Ruth
AU - Chess, Andrew
AU - Gulyás-Kovács, Attila
AU - Kassim, Bibi
AU - Xia, Eva
AU - Buxbaum, Joseph D.
AU - Sloofman, Laura
AU - Couto, Lizette
AU - Amaro, Mariana
AU - Iskhakova, Marina
AU - Breen, Michael
AU - Devillers, Olivia
AU - Akbarian, Schahram
AU - Jiang, Shan
AU - Kleopoulos, Steven P.
AU - Ma, Yixian
AU - Kim, Yungil
AU - Berretta, Sabina
AU - Mandal, Ajeet
AU - Lipska, Barbara K.
AU - McMahon, Francis
AU - Auluck, Pavan K.
AU - Marenco, Stefano
AU - Montgomery, Kelsey S.
AU - Peters, Mette A.
AU - Sieberts, Solveig K.
AU - Hahn, Chang Gyu
AU - Gur, Raquel
AU - Wang, Jiebiao
AU - Devlin, Bernie
AU - Lewis, David A.
AU - Klei, Lambertus
AU - Domenici, Enrico
AU - Ruderfer, Douglas M.
AU - Brennand, Kristen J.
AU - Haroutunian, Vahram
AU - Voloudakis, Georgios
AU - Fullard, John F.
AU - Roussos, Panos
N1 - Funding Information:
We thank the computational resources and staff expertise provided by the Scientific Computing group of the Icahn School of Medicine at Mount Sinai. The CommonMind data sets were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited; F. Hoffman-La Roche Ltd; and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, AG02219, AG05138, MH06692, R01MH110921, R01MH109677, R01MH109897, U01MH103392, U01MH116442, project ZIC MH002903 and contract HHSN271201300031C through the NIMH Intramural Research Program (IRP). Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh Brain Tissue Donation Program, and the NIMH Human Brain Collection Core. CMC leadership: P.R., J.D.B., A.C., S.A., V.H., B.D., D.A.L., R.G., C.-G.H., E.D., M.A.P., S.K.S., S.M., B.K.L. and F.J.M. This work is supported by the NIA through NIH grants R01-AG067025 (to P.R. and V.H.), R01-AG065582 (to P.R. and V.H.) and R01-AG050986 (to P.R.); by the NIMH through NIH grants R01-MH110921 (to P.R.), U01-MH116442 (to P.R. and V.H.), R01-MH125246 (to P.R.), R01-MH106056 (to P.R. and K.J.B.), R01-MH109897 (to P.R. and K.J.B.) and R01-MH121074 (to K.J.B.); and by the Veterans Affairs Merit grant BX002395 (to P.R.). P.D. was supported in part by NARSAD Young Investigator Grant 29683 from the Brain & Behavior Research Foundation. G.E.H. was supported in part by NARSAD Young Investigator Grant 26313 from the Brain & Behavior Research Foundation. J.B. was supported in part by NARSAD Young Investigator Grant 27209 from the Brain & Behavior Research Foundation.
Funding Information:
We thank the computational resources and staff expertise provided by the Scientific Computing group of the Icahn School of Medicine at Mount Sinai. The CommonMind data sets were generated as part of the CommonMind Consortium supported by funding from Takeda Pharmaceuticals Company Limited; F. Hoffman-La Roche Ltd; and NIH grants R01MH085542, R01MH093725, P50MH066392, P50MH080405, R01MH097276, RO1-MH-075916, P50M096891, P50MH084053S1, R37MH057881, AG02219, AG05138, MH06692, R01MH110921, R01MH109677, R01MH109897, U01MH103392, U01MH116442, project ZIC MH002903 and contract HHSN271201300031C through the NIMH Intramural Research Program (IRP). Brain tissue for the study was obtained from the following brain bank collections: the Mount Sinai/JJ Peters VA Medical Center NIH Brain and Tissue Repository, the University of Pennsylvania Alzheimer’s Disease Core Center, the University of Pittsburgh Brain Tissue Donation Program, and the NIMH Human Brain Collection Core. CMC leadership: P.R., J.D.B., A.C., S.A., V.H., B.D., D.A.L., R.G., C.-G.H., E.D., M.A.P., S.K.S., S.M., B.K.L. and F.J.M. This work is supported by the NIA through NIH grants R01-AG067025 (to P.R. and V.H.), R01-AG065582 (to P.R. and V.H.) and R01-AG050986 (to P.R.); by the NIMH through NIH grants R01-MH110921 (to P.R.), U01-MH116442 (to P.R. and V.H.), R01-MH125246 (to P.R.), R01-MH106056 (to P.R. and K.J.B.), R01-MH109897 (to P.R. and K.J.B.) and R01-MH121074 (to K.J.B.); and by the Veterans Affairs Merit grant BX002395 (to P.R.). P.D. was supported in part by NARSAD Young Investigator Grant 29683 from the Brain & Behavior Research Foundation. G.E.H. was supported in part by NARSAD Young Investigator Grant 26313 from the Brain & Behavior Research Foundation. J.B. was supported in part by NARSAD Young Investigator Grant 27209 from the Brain & Behavior Research Foundation.
Publisher Copyright:
© 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/10
Y1 - 2022/10
N2 - Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain. Besides regulating tissue-specific and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. By jointly analyzing large-scale cell-type-specific transcriptome and regulome data, we cataloged 30,795 neuronal and 23,265 non-neuronal candidate transcribed enhancers. Examination of the transcriptome in 1,382 brain samples identified robust expression of transcribed enhancers. We explored gene–enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified expression quantitative trait loci (eQTLs) for both genes and enhancers and found that enhancer eQTLs mediate a substantial fraction of neuropsychiatric trait heritability. Inclusion of enhancer eQTLs in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the gene–enhancer regulome and genetic mechanisms in the human cortex in both healthy and diseased states.
AB - Identification of risk variants for neuropsychiatric diseases within enhancers underscores the importance of understanding population-level variation in enhancer function in the human brain. Besides regulating tissue-specific and cell-type-specific transcription of target genes, enhancers themselves can be transcribed. By jointly analyzing large-scale cell-type-specific transcriptome and regulome data, we cataloged 30,795 neuronal and 23,265 non-neuronal candidate transcribed enhancers. Examination of the transcriptome in 1,382 brain samples identified robust expression of transcribed enhancers. We explored gene–enhancer coordination and found that enhancer-linked genes are strongly implicated in neuropsychiatric disease. We identified expression quantitative trait loci (eQTLs) for both genes and enhancers and found that enhancer eQTLs mediate a substantial fraction of neuropsychiatric trait heritability. Inclusion of enhancer eQTLs in transcriptome-wide association studies enhanced functional interpretation of disease loci. Overall, our study characterizes the gene–enhancer regulome and genetic mechanisms in the human cortex in both healthy and diseased states.
UR - http://www.scopus.com/inward/record.url?scp=85138877498&partnerID=8YFLogxK
U2 - 10.1038/s41588-022-01170-4
DO - 10.1038/s41588-022-01170-4
M3 - Article
C2 - 36163279
AN - SCOPUS:85138877498
VL - 54
SP - 1493
EP - 1503
JO - Nature Genetics
JF - Nature Genetics
SN - 1061-4036
IS - 10
ER -